Skin is the human body's first and best defense against environmental exposures including solar ultraviolet (UV) radiation. Exposure to UV light is a key factor in the development of skin disorders including cancer. Skin cancer is the most prevalent type of cancer in the United States, affecting an estimated one out of every seven Americans (Ndiaye, et al., Arch. Biochem. Biophys. (2011) 508: 164-70).
Nonmelanoma skin cancer (NMSC) has increased rapidly in the past two decades and more than one million new cases of non-melanoma skin cancer (NMSC) are diagnosed annually in the United States. It is suspected that this estimate is low as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) of the skin are not required to be reported and the number of actual cases annually is projected to be over 3 million new cases annually (Wheless, et al., “Nonmelanoma skin cancer and the risk of second primary cancers: a systematic review,” Cancer Epidemiol. Biomarkers Prey. (2010) 19: 1686-95). Based on IC9 Codes, it is estimated that 5% of the Medicare budget is used in the care of these patients (Rogers, et al., “Incidence estimate of nonmelanoma skin cancer in the United States, 2006,” Arch. Dermatol. (2010) 146: 283-7).
An estimated 2,700 deaths this year will be the result of NMSC in the US. The majority of these deaths are caused by SCC. Most NMSC, including SCC are caused by sun exposure (including UV-B light) with resultant photocarcinogenesis. Epidemiological data also shows an increased risk of other lethal cancer types in individuals with a history of skin cancer. Thus, it is vital to understand the harmful effects that UV light has on the skin so that effective methods of treatment or prevention can be developed.
Actinic keratoses (AKs) are precancerous cutaneous neoplasms, which can give rise to SCC. They arise as a result of long-term sun exposure. Other causes of AKs and NMSC are UV light from tanning booths or arc welding, x-irradiation, or exposure to certain chemicals. AKs are extremely common lesions and are present in more than 10 million Americans. In one sample population, the yearly rate of progression of an AK to a SCC in an average-risk person in Australia is between 8 and 24 per 10,000. High-risk individuals (those with multiple AKs) have progression rates as high as 12-30 percent over 3 years. Two percent of SCCs originating in AKs may metastasize, and 7 percent recur locally.
Actinic keratoses are treated most commonly with liquid nitrogen or a topical chemotherapeutic agent, such as, for example, 5-fluorouracil. Less commonly they are treated with other topical agents (diclofenac and imiquimod), photodynamic therapy, chemical peels or ablative laser resurfacing. Treatment for NMSC is usually surgical, often resulting in scarring and other morbidities.
In the instant specification, it will be understood that “actinic keratosis” is the proliferative disorder that produces AKs.
While some treatments are known, it would be desirable to proactively prevent or inhibit formation of actinic keratosis, hyperplasia, and/or skin cancers in order to reduce treatment costs, morbidity, and mortality. A lifetime of sun protection is an excellent method for minimizing risk of development of actinic keratosi, hyperplasia, and/or NMSC. However, a large percentage of patients already have extensive photodamage and changing sun-protective behaviors has proven to be difficult.
An ideal chemopreventive agent could achieve regression of precancerous changes, prevent development of NMSC and minimize ultraviolet light associated damage with minimal or no side effects. As noted above, there are topical agents that can remove actinic keratoses but they generally result in significant inflammation at the treatment site. A novel approach is required.
UV-mediated DNA Damage
Ultraviolet (UV) light plays an integral role in the development of numerous skin ailments ranging from aging to cancer. Considerable evidence spanning decades has conclusively demonstrated that UV radiation triggers multiple independent cellular responses. UV radiation is known to penetrate skin where it is absorbed by proteins, lipids and DNA, causing a series of events that result in progressive deterioration of the cellular structure and function of cells (Valacchi, et al., “Cutaneous responses to environmental stressors,” Ann. N. Y. Acad. Sci. (2012) 1271: 75-81). DNA is the building block of life and its stability is of the utmost importance for the proper functioning of all living cells. UV radiation is one of the most powerful (and common) environmental factors that can cause a wide range of cellular disorders by inducing mutagenic and cytotoxic DNA lesions; most notably cyclobutane-pyrimidine dimers (CPDs) and 6-4 photoproducts (64 pps) (Narayanan, et al., “Ultraviolet radiation and skin cancer,” Int. J. Dermatol. (2010) 49: 978-86). It is important to note that UV-mediated DNA damage is an early event in a plethora of proliferative cellular disorders. The two major types of UV-induced DNA damage are CPDs and 64 pp (along with their Dewer isomers) (Sinha, R. P. and Hader, D. P., “UV-induced DNA damage and repair: a review,” Photochem. Photobiol. Sci. (2002) 1: 225-36; and Rastogi, et al., “Molecular mechanisms of ultraviolet radiation-induced DNA damage and repair,” J. Nucleic Acids (2010) 2010: 592980). These abundant DNA lesions, if unrepaired, can interfere with DNA replication and subsequently cause mutations in DNA. Thus, these lesions can be mutagenic (potentially leading to proliferative disorders) and/or can be cytotoxic (resulting in cell death). 64 pp occur at about one third the frequency of CPDs, but are more mutagenic (Sinha & Hader, 2002). In one embodiment, prevention of these UV-mediated DNA adducts is paramount to guarding against the onset of several proliferative disorders, ranging from aging to cancer.
UV-mediated Hyperplasia
Increased keratinocyte proliferation, resulting in hyperplasia, is another major detrimental effect caused by UV exposure. This thickening of the skin is a direct result of the body trying to protect itself after excessive exposure to UV light. However, epidermal hyperplasia also increases the risk of skin cancer (Bowden, G. T., “Prevention of non-melanoma skin cancer by targeting ultraviolet-B-light signaling,” Nat. Rev. Cancer (2004) 4: 23-35). In another embodiment, prevention of UV-mediated hyperplasia is paramount to guarding against the onset of several proliferative disorders, ranging from aging to cancer.
UV-mediated Loss of Barrier Function
Maintaining a water-impermeable barrier between the organism and the environment is an essential function of skin. This barrier function serves to prevent dehydration; which can lead to death of the organism (Jiang, S. J., et al., “Ultraviolet B-induced alterations of the skin barrier and epidermal calcium gradient,” Exp. Dermatol. (2007) 16: 985-992). UV light has been demonstrated to disrupt epidermal skin barrier function in a dose-dependent manner (Haratake, A., et al., “UVB-induced alterations in permeability barrier function: roles for epidermal hyperproliferation and thymocyte-mediated response” J. Invest. Dermatol. (1997) 108: 769-775; and prey. citation). Skin barrier dysfunction can be directly assessed by measuring Transepidermal Water Loss (TEWL), which is a measure of skin hydration (Oba, C., et al., “Collagen hydrolysate intake improves the loss of epidermal barrier function and skin elasticity induced by UVB irradiation in hairless mice,” Photodermatol. Photoimmunol. Photomed. (2013) 29: 204-11; and prey. citations).
Resveratrol, a natural polyphenol present in grapes and red wine, exerts several beneficial effects including antioxidant, chemopreventative and cardioprotective (Park, K. and Lee, J- H., “Protective effects of resveratrol on UVB-irradiated HaCaT cells through attenuation of the caspase pathway,” Oncol. Rep. (2008) 19: 413-7). Several studies have shown that resveratrol prevents UV-B mediated cell damage (including hyperplasia) in mouse skin when given orally or applied topically (Afaq, F., et al., “Prevention of short-term ultraviolet B radiation-mediated damages by resveratrol in SKH-1 hairless mice,” Toxicol. Appl. Pharmacol. (2003) 186(1): 28-37; Reagan-Shaw, S., et al., “Modulations of critical cell cycle regulatory events during chemoprevention of ultraviolet B-mediated responses by resveratrol in SKH-1 hairless mouse skin,” Oncogene (2004) 23(30): 5151-60; Aziz, M. H., et al., “Prevention of ultraviolet-B radiation damage by resveratrol in mouse skin is mediated via modulation in survivin,” Photochem. Photobiol. (2005) 81(1): 25-31; and Kim, K. H., et al. “Resveratrol Targets Transforming Growth Factor-beta2 Signaling to Block UV-Induced Tumor Progression,” J. Invest. Dermatol. (2011) 131: 195-202). Resveratrol has been shown to block UV-induced skin cancer progression in several mouse studies (Athar, M., et al., “Resveratrol: a review of preclinical studies for human cancer prevention,” Toxicol. Appl. Pharmacol. (2007) 224: 274-83). However, its use in humans as a chemopreventative agent seems to be unlikely (at least as a single agent) due to poor bioavailability (Roupe, K. A., et al. “Pharmacometrics of stilbenes: seguing towards the clinic,” Curr. Clin. Pharmacol. (2006) 1: 81-101). Resveratrol is well tolerated in humans, but is readily metabolized (by the UGTs) leading to a short half-life which hinders its effectiveness as a chemopreventative agent (Cottart C. H., et al., “Resveratrol bioavailability and toxicity in humans,” Mol. Nutr. Food Res. (2010) 54: 7-16).